tbuckley/cabot-search huggingface dataset:
Abstract P3110: Mechanism Of Cardiotoxicity Associated With Tyrosine Kinase Inhibitor Osimertinib
Authors: Anand P Singh, Claire Castro, Abhilasha Shiv Chandra Singh, Haobo Li, Cedric D Sheffield, Kangsan Roh, Jason D Roh, Anthony Rosenzweig
Journal: Circulation Research (2022)

Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for non-small cell lung cancer (NSCLC) treatment. Osimertinib potently and selectively inhibits EGFR-T790M resistance mutations in patients with NSCLC harboring these mutations. Emerging evidence from clinical trials has identified potential cardiotoxic effects of osimertinib including heart failure, atrial fibrillation (AF), and QT interval prolongation. The mechanisms underlying osimertinib-induced cardiotoxicity, however, are poorly understood. Methods: To investigate potential mechanisms of osimertinib-induced cardiotoxicity, we tested the drug in both in vitro cultured cardiomyocytes (CMs) and wild-type C57BL/6 mice in vivo , corresponding to doses used in preclinical development. Echocardiography was performed in mice to assess the effect on cardiac function. In vivo electrophysiology studies were also performed to assess effects on osimertinib-induced AF and QT prolongation susceptibility. Results: Osimertinib (500 nM, 72 hours) reduced CM viability in NRVMs (p=0.0001), and induced apoptosis as determined by TUNEL assay (p=0.004) and upregulated Bax/Bcl-2 ratio (mRNA: 1.45-fold, p=0.001). In wild-type C57BL/6 mice, osimertinib (5 mg/Kg/day, 4 weeks) decreased ejection fraction (37.15±3.99% vs control: 51.04±2.23%, p=0.0001) and fractional shortening (17.69±2.18% vs control: 25.56±1.51%, p=0.0001). This was associated with an increase in cardiac BNP expression (mRNA: 1.72-fold, p=0.005) and apoptotic Bax/Bcl-2 ratio (protein: 1.85-fold, p=0.02). Electrophysiology studies also demonstrated 2:1 atrioventricular block (p=0.03) in osimertinib treated mice and increased AF susceptibility. A combination of in vitro and in vivo mechanistic analyses demonstrated that osimertinib significantly inhibits pro-survival ERK signaling pathway. Conclusions: Our results demonstrate that the cardiotoxicity seen with osimertinib in clinical trials is largely recapitulated in preclinical models, and that osimertinib can directly induce CM death. These models may provide a foundation for further investigating mechanism of osimertinib-induced cardiotoxicity and interventions to mitigate it.
Management of occupational asthma
Authors: DJ Hendrick
Journal: European Respiratory Journal (1994)

The importance of occupational asthma and its management is usefully set in perspective by considering recent trends of increasing asthma incidence, morbidity and mortality in the population at large. The contribution to incidence made by asthma of occupational origin is of the order 20-100 cases per million workers per year; the individual worker's lifetime risk approaching 5% in some industrial environments. Management of the affected industry inevitably follows different pathways from that of the affected individual, though both need to start from a definitive diagnosis. For the affected industry, managers must identify the causative agent and assess the extent of the problem. Affected workers can then be removed from hazardous settings, and meaningful strategies of prevention can be introduced. The most promising preventive measures involve improvements in industrial hygiene or the substitution of alternative agents in the manufacturing process. The role of worker selection (i.e. the exclusion of applicant workers who may be unduly susceptible because they smoke, or have existing airway hyperresponsiveness or atopy) is small and controversial. More valuable is a strict surveillance programme of workers perceived to be at risk, so that emerging disease is recognized promptly, before it poses any major threat of permanent ill-health. Management choices beyond conventional medication and the avoidance of irritant environmental triggers are greatly limited for the affected individual worker. A change of job environment with complete cessation of exposure to the relevant asthma-inducing agent is to be favoured and offers the best chance of full recovery, but may not be practical if the worker is to avoid permanent unemployment.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract P3139: A Pluripotent Stem Cell Model Of Nilotinib-induced Arterial Disease
Authors: Emily A Pinheiro, Paul W Burridge
Journal: Circulation Research (2022)

Nilotinib is a highly effective tyrosine kinase inhibitor used to treat Chronic Myeloid Leukemia (CML). While nilotinib successfully treats CML, a common and serious side effect is development of nilotinib-induced arterial disease (NAD) even in patients without pre-existing risk factors. This side effect is not seen with imatinib, a CML drug in the same class that inhibits the same target as nilotinib. To date, the mechanisms of NAD are unknown, and the cell types involved in this adverse effect have yet to be identified. Furthermore, no tools currently exist to predict which patients will develop NAD. In this study, we used endothelial and vascular smooth cells derived from human-induced pluripotent stem cells (hiPSCs) as a model to identify which cell types are involved in NAD and which cellular functions are perturbed. We first developed a set of efficient, reproducible endothelial and vascular smooth muscle differentiation and purification protocols that consistently yield &gt;95% pure cells. For both hiPSC-derived endothelial cells (hiPSC-ECs) and hiPSC-derived vascular smooth muscle cells (hiPSC-VSMCs) we next identified a panel of assays relevant to various functions of atherogenesis. In comparing the effects of nilotinib and imatinib on hiPSC-ECs, we see a nilotinib-specific decrease in cell capacity for proliferation and migration, in addition to disturbances in Ac-LDL uptake and NO homeostasis. Nilotinib is not differentially toxic to hiPSC-ECs compared to imatinib and has no effect on barrier function as measured by multielectrode array. The data collected to date demonstrate the feasibility of using hiPSCs to model NAD in vitro and recapitulate the clinical discrepancy in vascular effects between nilotinib and imatinib.
MRI Coil Development Strategies for Hybrid MR-PET Systems: A Review
Authors: Chang-Hoon Choi, Jörg Felder, Christoph Lerche, N. Jon Shah
Journal: IEEE Reviews in Biomedical Engineering (2022)

Simultaneously operating MR-PET systems have the potential to provide synergetic multi-parametric information, and, as such, interest surrounding their use and development is increasing. However, despite the potential advantages offered by fully combined MR-PET systems, implementing this hybrid integration is technically laborious, and any factors degrading the quality of either modality must be circumvented to ensure optimal performance. In order to attain the best possible quality from both systems, most full MR-PET integrations tend to place the shielded PET system inside the MRI system, close to the target volume of the subject. The radiofrequency (RF) coil used in MRI systems is a key factor in determining the quality of the MR images, and, in simultaneous acquisition, it is generally positioned inside the PET system and PET imaging region, potentially resulting in attenuation and artefacts in the PET images. Therefore, when designing hybrid MR-PET systems, it is imperative that consideration be given to the RF coils inside the PET system. In this review, we present current state-of-the-art RF coil designs used for hybrid MR-PET experiments and discuss various design strategies for constructing PET transparent RF coils.
Abstract P1015: Construction Of A Pro-cardiogenic Extracellular Matrix: How Stem-cell Derived Epicardium Enhances Cardiac Regeneration Through Fibronectin
Authors: Jonathan C Lee, Lay Ping Ong, Semih Bayraktar, Patrick Rericha, Vincent Knight-Schrijver, Maria Colzani, Johannes Bargehr, Laure Gambardella, Sanjay Sinha
Journal: Circulation Research (2022)

Background: Human embryonic stem cell-derived epicardium (hESC-Epis) has been shown to improve the function of hESC-derived cardiomyocytes (hESC-CM) in vitro and post-transplantation into animal myocardial infarction models. However, the underlying mechanisms mediating these effects remain poorly characterised. Bulk RNA sequencing of hESC-Epis suggests a role for genes related to extracellular matrix remodeling in mediating these effects, with fibronectin (FN1) being highly implicated. Study Objective: To examine the role of FN1 in hESC-CM/Epi crosstalk through gain and loss of function studies. Methods: A tetracycline inducible FN1 knockdown system was used on hESC-CMs and Epis within the setting of 3D-engineered heart tissue. Changes in contractility and calcium handling were measured. Recombinant human plasma FN1 (rhFN) was then used to determine the effect of FN1 supplementation on hESC-CM function. Results: FN1 knockdown in hESC-Epis resulted in significant abrogation of the beneficial effects on hESC-CM force generation and calcium handling. Knockdown of FN1 in hESC-CMs however significantly attenuated contractility of the hESC-CMs but had no effects on calcium handling. When rhFN was added to hESC-CMs in increasing doses, hESC-CM contractility was improved in a dose dependent fashion to the same extent as seen with hESC-Epis co-cultures. However, rhFN supplementation did not result in significant improvements in calcium handling. Conclusions: hESC-CM and Epi crosstalk improving hESC-CM function may rely heavily on the presence of FN1. FN1 secreted by both cell types are shown to be of importance in this crosstalk with artificial supplementation of rhFN being able to recapitulate some beneficial effects of hESC-Epis on hESC-CMs. Further studies are required to determine the role of specific isoforms of secreted FN1 on hESC-CM maturity and what mechanism underlies these effects. This opens up the possibility of improving cell-based therapy for heart failure post-myocardial infarction using recombinant FN1 supplementation.
Abstract P3098: Histone Modifying Genes In Heart Development And Disease
Authors: Junyi Zhu, Hangnoh Lee, Joyce van de Leemput, Zhe Han
Journal: Circulation Research (2022)

Sequencing of Congenital Heart Disease (CHD) patients identified variants in many histone modifying genes, suggesting that histone modification plays important roles in heart development and disease. However, how these histone modifying genes perform their epigenetic regulation function during heart development remain elusive, and whether these novel genetic variants identified from CHD patients are causal remain unclear. We found that most histone modifying genes are highly conserved from Drosophila to humans, and many are expressed in the developing heart in both systems. Using a high-throughput functional validation system that we generated for providing the “gene-level” disease association for candidate CHD genes, we screened lots of histone-modifying genes and identified many that are required for heart development in Drosophila. Among them, genes involved in histone H3K4 mono- and dimethylation are particularly important for heart development and appear to regulate evolutionarily conserved targets during heart development from Drosophila to mammals. We also generated Drosophila models for CHD patient-derived variants in histone-modifying genes to study how these variants affect the function of the human genes in the context of the fly heart development, to provide the “variant-level” evidence for their causal association with CHD.
Abstract P3122: Latent Mouse Model Of HIV-1
Authors: Olena Kondrachuk, Jay Rappaport, Manish K Gupta
Journal: Circulation Research (2022)

Background: Antiretroviral therapy (ART) significantly improves the life span of people living with HIV/AIDS (PLWHA). However, HIV- associated cardiovascular diseases (CVDs) remain one of the leading causes of heart failure and comorbidity in PLWHA. Modern ART regimens reduce viral loads to undetectable levels in HIV+ patients while being less toxic. Nevertheless, HIV proteins are present in the plasma of PLWHA. The HIV protein, Nef, has been found circulating in the plasma of ART-treated patients within extracellular vesicles and in association with immune cells. We hypothesized that circulating HIV Nef proteins may cause an adverse effect on various organ functions. To further understand the effect of Nef on differing organ functions, we have generated a transgenic mouse model which expresses the Nef protein in the presence of Cre recombinase. Methods and Results: Nef transgenic mouse model was generated by cloning HIV-1 Nef ORF in CAG-Lox-CAT vector. Transgenic mice lines were crossed with the alpha myosin heavy chain promoter Cre mice to express Nef protein in the heart. Western blot data validated Nef protein expression in the adult mouse heart. Histological evaluation of the effect of Nef protein expression on heart morphology revealed cardiac hypertrophy. Furthermore, heart function analysis shows that Nef expressing mouse lines have depressed heart function. Conclusion: Our study suggests that Nef causes cardiac dysfunction that mimics cardiomyopathy secondary to latent HIV in PLWHA. Further, this mouse model could be useful in studying the effect of Nef protein in different organs or cells using cell-specific Cre recombinase. Moreover, Nef transgenic mice could be useful in generating new therapeutic tools to control comorbidity in PLWHA.
SREBP signaling is essential for effective B cell responses
Authors: Wei Luo, Julia Z. Adamska, Chunfeng Li, Rohit Verma, Qing Liu, Thomas Hagan, Florian Wimmers, Shakti Gupta, Yupeng Feng, Wenxia Jiang, Jiehao Zhou, Erika Valore, Yanli Wang, Meera Trisal, Shankar Subramaniam, Timothy F. Osborne, Bali Pulendran
Journal: Nature Immunology (2022)
Melatonin for prevention of acute kidney injury in patients treated with intravenous polymyxin B: a double-blind, placebo-controlled randomized clinical trial
Authors: Maria H. Rigatto, Pedro Bergo, Giulia Baldissera, Eduarda Beck, Leonardo David, Lucas Santoro, Andressa Barros, Rafael Zanin, João I. Budelon Gonçalves, Diego Falci, Wolnei Caumo, Alexandre P. Zavascki
Journal: Clinical Microbiology and Infection (2022)
3D bioprinting and its innovative approach for biomedical applications
Authors: Swikriti Tripathi, Subham Shekhar Mandal, Sudepta Bauri, Pralay Maiti
Journal: MedComm (2022)

Abstract 3D bioprinting or additive manufacturing is an emerging innovative technology revolutionizing the field of biomedical applications by combining engineering, manufacturing, art, education, and medicine. This process involved incorporating the cells with biocompatible materials to design the required tissue or organ model in situ for various in vivo applications. Conventional 3D printing is involved in constructing the model without incorporating any living components, thereby limiting its use in several recent biological applications. However, this uses additional biological complexities, including material choice, cell types, and their growth and differentiation factors. This state‐of‐the‐art technology consciously summarizes different methods used in bioprinting and their importance and setbacks. It also elaborates on the concept of bioinks and their utility. Biomedical applications such as cancer therapy, tissue engineering, bone regeneration, and wound healing involving 3D printing have gained much attention in recent years. This article aims to provide a comprehensive review of all the aspects associated with 3D bioprinting, from material selection, technology, and fabrication to applications in the biomedical fields. Attempts have been made to highlight each element in detail, along with the associated available reports from recent literature. This review focuses on providing a single platform for cancer and tissue engineering applications associated with 3D bioprinting in the biomedical field.
Copper-cysteamine nanoparticle-mediated microwave dynamic therapy improves cancer treatment with induction of ferroptosis
Authors: Hui Zhou, Zhongtao Liu, Zijian Zhang, Nil Kanatha Pandey, Eric Amador, William Nguyen, Lalit Chudal, Li Xiong, Wei Chen, Yu Wen
Journal: Bioactive Materials (2022)

Photodynamic Therapy (PDT) holds a great promise for cancer patients, however, due to the hypoxic characteristics of most solid tumors and the limited penetration depth of light in tissues, the extensive clinical application of PDT is limited. Herein, we report microwave induced copper-cysteamine (Cu-Cy) nanoparticles-based PDT as a promising cancer treatment to overcome cancer resistance in combination with ferroptosis. The treatment efficiency of Cu-Cy-mediated microwave dynamic therapy (MWDT) tested on HCT15 colorectal cancer (CRC) cells via cell titer-blue cell viability assay and live/dead assay reveal that Cu-Cy upon MW irradiation can effectively destroy HCT15 CRC cells with average IC-50 values of 20 μg/mL. The cytotoxicity of Cu-Cy to tumor cells after MW stimulation can be alleviated by ferroptosis inhibitor. Furthermore, Cu-Cy mediated MWDT could deplete glutathione peroxide 4 (GPX4) and enhance lipid peroxides (LPO) and malondialdehyde (MDA). Our findings demonstrate that MW-activated Cu-Cy killed CRC cells by inducing ferroptosis. The superior in vivo antitumor efficacy of the Cu-Cy was corroborated by a HCT15 tumor-bearing mice model. Immunohistochemical experiments showed that the GPX4 expression level in Cu-Cy + MW group was significantly lower than that in other groups. Overall, these findings demonstrate that Cu-Cy nanoparticles have a safe and promising clinical application prospect in MWDT for deep-seated tumors and effectively inhibit tumor cell proliferation by inducing ferroptosis, which provides a potential solution for cancer resistance.
Prevalence and Professional Impact of Mental Health Conditions Among Cardiologists
Authors: Garima Sharma, Shiavax J. Rao, Pamela S. Douglas, Anne Rzeszut, Dipti Itchhaporia, Malissa J. Wood, Khurram Nasir, Roger S. Blumenthal, Athena Poppas, Jeffrey Kuvin, Andrew P. Miller, Roxana Mehran, Michael Valentine, Richard F. Summers, Laxmi S. Mehta
Journal: Journal of the American College of Cardiology (2022)
Cardiovascular Disease Among Persons Living With HIV: New Insights Into Pathogenesis and Clinical Manifestations in a Global Context
Authors: Mpiko Ntsekhe, Jason V. Baker
Journal: Circulation (2022)

Widespread use of contemporary antiretroviral therapy globally has transformed HIV disease into a chronic illness associated with excess risk for disorders of the heart and circulatory system. Current clinical care and research has focused on improving HIV-related cardiovascular disease outcomes, survival, and quality of life. In high-income countries, emphasis on prevention of atherosclerotic coronary artery disease over the past decade, including aggressive management of traditional risk factors and earlier initiation of antiretroviral therapy, has reduced risk for myocardial infarction among persons living with human immunodeficiency virus-1 infection. Still, across the globe, persons living with human immunodeficiency virus-1 infection on effective antiretroviral therapy treatment remain at increased risk for ischemic outcomes such as myocardial infarction and stroke relative to the persons without HIV. Unique features of HIV-related cardiovascular disease, in part, include the pathogenesis of coronary disease characterized by remodeling ectasia and unusual plaque morphology, the relative high proportion of type 2 myocardial infarction events, abnormalities of the aorta such as aneurysms and diffuse aortic inflammation, and HIV cerebrovasculopathy as a contributor to stroke risk. Literature over the past decade has also reflected a shift in the profile and prevalence of HIV-associated heart failure, with a reduced but persistent risk of heart failure with reduced ejection fraction and a growing risk of heart failure with preserved ejection fraction. Cardiac magnetic resonance imaging and autopsy data have emphasized the central importance of intramyocardial fibrosis for the pathogenesis of both heart failure with preserved ejection fraction and the increase in risk of sudden cardiac death. Still, more research is needed to better characterize the underlying mechanisms and clinical phenotype of HIV-associated myocardial disease in the current era. Across the different cardiovascular disease manifestations, a common pathogenic feature is that HIV-associated inflammation working through different mechanisms may amplify underlying pathology because of traditional risk and other host factors. The prevalence and phenotype of individual cardiovascular disease manifestations is ultimately influenced by the degree of injury from HIV disease combined with the profile of underlying cardiometabolic factors, both of which may differ substantially by region globally.
Tackling Adversity and Cardiovascular Health: It is About Time
Authors: Sarah K. Westcott, Tené T. Lewis, Michelle A. Albert
Journal: Circulation (2022)

ne of the most foundational shared human experiences is adversity.Defined by Merriam-Webster Dictionary as "a state or instance of serious or continued difficulty or misfortune, " adversity can catalyze personal development and shape our values.However, the potency, life-course timing, duration, and type of adversity an individual or population faces affect biological adaptation, psychosocial responses, and health behaviors.Experiences with adversity, particularly when long term, lead to untoward health and wellbeing.This effect is markedly evident within the realm of cardiovascular disease.Certainly, decades of primary research, especially in the psychosocial literature, documents associations between various types of adversity and both cardiovascular risk factors and disease.Categories of adversity include but are not limited to exposure to harsh childhood environments, life-course trauma, violence, discrimination, economic and neighborhood stressors, environmental disasters, and even sociopolitical anxiety.For example, self-reported everyday discrimination is positively associated with hypertension, poor sleep, visceral fat, elevated C-reactive protein levels, coronary artery calcification, and mortality. 1In addition, exposure to a single traumatic life event such as violence or death of someone close is related to higher odds of atrial fibrillation. 2sychosocial stress (stress) represents a core component of adversity.However, stress is not always health damaging.For example, manageable amounts of psychosocial stress, if associated with adequate social and emotional support, along with mastery and control, may preserve healthy brain architecture.However, cumulative chronic stress (cumulative stress), defined
Moving research direction in the field of metallic bioresorbable stents-A mini-review
Authors: Xiehui Chen, Rong Chang, Hongtao Liu, Le Zhang, Yufeng Zheng
Journal: Bioactive Materials (2022)

In contrast to polymer bioresorbable stents (BRS) that exhibited suboptimal performance in clinical trials due to their deficient mechanical properties, metallic BRS with improved mechanical strength have made their way into the clinic and have demonstrated more promising results. In the roadmap of research and development of metallic BRS, magnesium and iron based biodegradable metal stents had been clinically used, and the zinc based biodegradable metal stents had been trailed in Mini-Pigs. In this mini-review paper, we demonstrate the current technology levels and point out the future R&D direction of metallic BRS. Magnesium based BRS should target for decreasing struct thickness meanwhile balancing with enough supporting strength. Iron based BRS should move towards high efficient absorption, conversion, metabolism, elimination of its degradation products. Zn based BRS should strive to improve mechanical stability, creep resistance and biocompatibility. Future R&D directions of metallic BRS should move towards new materials such as Molybdenum, intelligent stent integrated with degradable biosensors, and new stent with multiple biofunctions, such as NO release.